WO2011034397A2 - Méthode de prédiction de cibles de médicament et criblage de médicaments destinés à détecter des microorganismes pathogènes au moyen de métabolites essentiels - Google Patents

Méthode de prédiction de cibles de médicament et criblage de médicaments destinés à détecter des microorganismes pathogènes au moyen de métabolites essentiels Download PDF

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WO2011034397A2
WO2011034397A2 PCT/KR2010/006469 KR2010006469W WO2011034397A2 WO 2011034397 A2 WO2011034397 A2 WO 2011034397A2 KR 2010006469 W KR2010006469 W KR 2010006469W WO 2011034397 A2 WO2011034397 A2 WO 2011034397A2
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essential
metabolite
phosphate
metabolism
metabolites
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WO2011034397A3 (fr
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이상엽
김현욱
김태용
이규양
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한국과학기술원
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    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B5/00—ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks

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  • the present invention relates to a method for predicting a drug target and a drug search method of a pathogenic microorganism using computer system technology, and more specifically, selecting a target microorganism, constructing a metabolic network model of the selected microorganism, and then analyzing essential metabolite (metabolite). essentiality, removal of circulation metabolite, consideration of the number of reaction schemes, methods of predicting drug targets using irrelevance to host metabolism, and antimicrobial drugs from compounds with structural similarities to the selected essential metabolites. It relates to a method of screening.
  • Pathogenic microorganisms can be very difficult and fatal to treat if they occur in people with weakened immune systems. Therefore, efforts to find a target for the development of effective anti-pathogenic drugs of pathogenic microorganisms are active.
  • Metabolic flow analysis uses the mass balance and cell composition information of biochemical equations to obtain the ideal metabolic flow space that cells can reach, and aims to maximize or minimize specific objective functions through optimization methods (maximization of cell growth rate or specific perturbation). Minimization of metabolic regulation by
  • metabolic flow analysis can generally be used to confirm the lethality of specific genes of a desired metabolite through strain improvement, and can be used to determine the metabolic network characteristics within the strain.
  • various studies have been reported applying metabolic flow analysis methods to predict the flow changes in metabolic networks caused by the removal or addition of genes.
  • metabolic flow analysis techniques can be used to look at the metabolism of complex microorganisms from a holistic perspective using partial metabolic information and to identify the effects of manipulation on specific genes on overall metabolic flow to accurately predict drug targets of pathogenic microorganisms. There is an urgent need for the development of such methods.
  • the present inventors constructed a metabolic network model of the microbial pathogens Acinetobacter baumannii and Vibrio vulnificus , and then applied a metabolite analysis method to the metabolic model. Predict metabolites that are essential for growth, remove those of the current metabolite, and those that consume less than the required number of reaction metabolites, and the remaining essential metabolites and enzymes that consume them Theoretically discovered that only the missing ones could be selected and selected as potential candidates to predict efficient pathogen drug targets. Finally, compounds that are structurally similar to the essential metabolites selected were selected for anti-pathogenic candidates. The material was explored and the present invention was completed.
  • An object of the present invention is to build a microbial metabolic network model structure, using the essential metabolite analysis (metabolite essentiality), distribution metabolite removal (currency metabolite) removal, considering the number of reactions, the relationship between the host metabolism,
  • the present invention provides a method for screening an enzyme or a gene encoding the same as a drug target.
  • Another object of the present invention is to provide a method for screening an enzyme or a gene encoding the enzyme that is a drug target of the genus Acinetobacter using the above method.
  • Another object of the present invention is to provide a method for screening an enzyme or a gene encoding the enzyme that is a drug target of Vibrio genus microorganisms using the above method.
  • Still another object of the present invention is to provide enzymes which are drug targets against Acinetobacter sp. Microorganisms obtained by the above method and gene groups encoding them.
  • Still another object of the present invention is to provide drug target enzymes for Vibrio genus microorganisms and gene groups encoding them, which are obtained by the above method.
  • Another object of the present invention is an enzyme of the selected microorganism; Or it provides a method of using the determined gene of the target microorganism as a drug target of the target microorganism.
  • Another object of the present invention is to determine essential metabolites based on the structure of a particular microbial metabolic network model, using essential metabolite analysis, distribution metabolite removal, number of reaction schemes, and non-relevance to host metabolism.
  • a structurally similar compound is selected from a compound library to provide a method for screening drugs that can inhibit the growth of a target microorganism through microbial growth inhibition experiments.
  • Another object of the present invention is based on the structure of the metabolic network model of the genus Acinetobacter Baumani or Vibrio vulnificus , to analyze essential metabolites, remove distribution metabolites, consider the number of reaction schemes, and compare with host metabolism. Relevance is used to determine essential metabolites, and structurally similar compounds are selected from compound libraries using Tanimoto coefficients to screen for drugs that can inhibit the growth of target microorganisms through microbial pathogen growth inhibition experiments. To provide a method.
  • acinetobacter Baumani obtained through the above method It is to provide a drug that can inhibit the growth of certain microorganisms, including the genus microorganism or Vibrio bulnipius genus and an antimicrobial composition containing the same.
  • At least three or more enzymes are involved in the reaction scheme, and at the same time, at least two or more of the essential metabolites consume the corresponding metabolites.
  • step (c) determining a secondary essential metabolite by removing a circulation metabolite having no specificity with the target microorganism among the first essential metabolites determined in step (b);
  • step (e) selecting only those which are not present in the metabolism of the host among the third essential metabolites determined in step (d) and determining the fourth essential metabolite;
  • step (f) if all of the enzymes consuming the fourth essential metabolites determined in step (e) do not have homology with the host protein, the corresponding metabolites are determined as the fifth essential metabolite, and the fifth essential metabolite It provides a method for screening a drug target enzyme of a microorganism comprising the step of selecting an enzyme involved in the drug target enzyme of the target microorganism.
  • the present invention provides a method for screening a drug target gene for a microorganism, characterized in that the gene group encoding the drug target enzyme of the selected microorganism is determined as a drug target gene of the target microorganism.
  • the host may be a human, and the target microorganism is preferably Escherichia coli or pathogenic microorganism, and more preferably pathogenic microorganism.
  • the metabolic network of the microorganism in step (a) is genomic level, and performing the step (b),
  • Vjm is a metabolic flow value of the corresponding consumption equation
  • the application of the linear programming is preferably made by reflecting all the nutrient conditions necessary for the growth of cells.
  • the distribution metabolite having no specificity with the target microorganism in step (c) is also involved in other enzymatic reactions of the target microorganism and other organisms, and in step (d), at least three or more of the secondary essential metabolites At least two or more at the same time involved in the enzymatic reaction, it is preferable to determine the metabolite in the case of consuming the required metabolite as the third essential metabolite, and in step (f) the examination of the homology is carried out Gene sequences can be used. At this time, the examination of the homology may be performed using the BLASTP program or the BLAST program.
  • the present invention provides the enzymes of the selected microorganism or gene groups encoding the same, and a method of using them as drug targets of the microorganism.
  • step (e) selecting a compound candidate group having structural similarity to the essential metabolite in step (d) from the compound library by using Tanimoto coefficients;
  • It provides a drug screening method for microorganisms, including.
  • step (c) determining a secondary essential metabolite by removing a circulation metabolite having no specificity with the target microorganism among the first essential metabolites determined in step (b);
  • step (d) determining the third essential metabolite in consideration of the number of enzymatic schemes involved and the number of enzymatic schemes consumed among the secondary essential metabolites determined in step (c);
  • step (e) selecting only those which are not present in the metabolism of the host among the third essential metabolites determined in step (d) and determining the fourth essential metabolite;
  • step (f) if all the enzymes consuming the fourth essential metabolites determined in step (e) do not have a homology with the host protein, determining those essential metabolites as the fifth essential metabolite;
  • step (g) selecting a compound candidate group having structural similarity to the fifth essential metabolite in step (e) from the compound library by using a Tanimoto coefficient;
  • screening drugs by administering each of the selected compound candidate groups to target microorganisms to determine whether they inhibit growth.
  • It provides a method for screening a drug against a microorganism, including.
  • step (c) Among the primary essential metabolites determined in step (b), the secondary essential metabolite is removed by removing a circulation metabolite having no specificity with the microorganisms of the genus Acinetobacter . Determining;
  • step (d) determining the third essential metabolite in consideration of the number of enzymatic schemes involved and the number of enzymatic schemes consumed among the secondary essential metabolites determined in step (c); (e) selecting only those which are not present in the metabolism of the host among the third essential metabolites determined in step (d) and determining the fourth essential metabolite;
  • step (f) if all of the enzymes consuming the fourth essential metabolites determined in step (e) do not have homology with the host protein, the corresponding metabolites are determined as the fifth essential metabolite, and the fifth essential metabolite enzymes involved in providing the Acinetobacter drug screening method of the target enzyme of the microorganism of the genus Acinetobacter (Acinetobacter), comprising the step of selecting the drug for the target enzyme in microorganisms (Acinetobacter).
  • Acinetobacter Acinetobacter
  • Acinetobacter baumannii Acinetobacter baumannii
  • 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine, pyrophosphokinase, dihydropteroate synthase, glutamate racemase, UDP-N-acetylmuramoylalanine--D-glutamate ligase, dihydrodipicolinate reductase, dihydroneopterin aldolase, alkaline phosphatase D precursor, 3-dehydroquinate dehydratase II, catabo 3-dehydroquinate dehydratase (3-dehydroquinase), shikimate 5-dehydrogenase, quinate / shikimate dehydrogenase, 3-dehydroshikimate dehydratase, 1-deoxy-D-xylulose-5-phosphate reductoisomerase, pyridoxine 5-phosphate synthase, 3-deoxy-manno- Enzyme group of the genus Acinetobacter selected from the group
  • step (c) Among the primary essential metabolites determined in step (b), the secondary essential metabolite is determined by removing a circulation metabolite having no specificity with Vibrio genus microorganisms. step;
  • step (d) determining the third essential metabolite in consideration of the number of enzymatic schemes involved and the number of enzymatic schemes consumed among the secondary essential metabolites determined in step (c);
  • step (e) selecting only those which are not present in the metabolism of the host among the third essential metabolites determined in step (d) and determining the fourth essential metabolite;
  • step (f) if all of the enzymes consuming the fourth essential metabolites determined in step (e) do not have homology with the host protein, the corresponding metabolites are determined as the fifth essential metabolite, and the fifth essential metabolite enzymes involved in including the step of selecting the drug target enzyme of the microorganism of the genus Vibrio (Vibrio), provides a screening method of Vibrio drug target of the enzyme in microorganisms (Vibrio).
  • step (c) Among the primary essential metabolites determined in step (b), the secondary essential metabolite is determined by removing a circulation metabolite having no specificity with Vibrio genus microorganisms. step;
  • step (d) determining the third essential metabolite in consideration of the number of enzymatic schemes involved and the number of enzymatic schemes consumed among the secondary essential metabolites determined in step (c);
  • step (e) selecting only those which are not present in the metabolism of the host among the third essential metabolites determined in step (d) and determining the fourth essential metabolite;
  • step (f) if all the enzymes consuming the fourth essential metabolites determined in step (e) do not have a homology with the host protein, determining those essential metabolites as the fifth essential metabolite;
  • step (g) selecting a compound candidate group having structural similarity to the fifth essential metabolite in step (f) from the compound library by using Tanimoto coefficients;
  • (h) provides a drug screening method for by checking whether the growth inhibition by administering the selected compound candidate for each Vibrio (Vibrio) into the microorganism comprising the step of screening a drug, Vibrio (Vibrio) spp.
  • the present invention also provides 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase, dihydropteroate synthase, glutamate racemase, UDP-N-acetylmuramoylalanine--D-glutamate ligase, dihydrodipicolinate reductase, 1-deoxy-D-xylulose-5-phosphate one or more Vibrio genus microbial enzymes selected from the group consisting of reductoisomerase, pyridoxine 5-phosphate synthase, and methods for using them as drug targets, and VV10567 and VV10580 genes encoding the enzymes obtained by the method , VV11175, VV11568, VV11644, VV11691 and VV11866, one or more Vibrio genus microbial genes selected from the group consisting of, and methods of using them as drug targets.
  • the present invention is also screened according to the above method, and has a structure of Formula 1, Vibrio ( Vibrio ) It provides a compound having an antimicrobial activity against the genus microorganisms and an antimicrobial composition containing the same:
  • FIG. 1 is a schematic diagram illustrating the concept of a microbial drug targeting methodology in accordance with the present invention
  • A building a metabolic network of specific microorganisms
  • B Primary essential metabolite prediction using essential metabolite analysis
  • C removal of distribution metabolites
  • D Consider the number of schemes involved in that metabolite
  • E confirm presence in host metabolism
  • F drug target enzyme and gene determination
  • FIG. 2 is a schematic diagram illustrating the microbial growth inhibition experiment by selecting a compound similar to the structure of five fifth essential metabolites from the compound library as a drug candidate for Vibrio genus microorganisms.
  • the present invention in one aspect, relates to a method for screening drug target enzymes or drug target genes encoding the microorganisms, in particular pathogenic microorganisms.
  • the schematic process is shown in FIG.
  • FIG. 1 illustrates the concept of an integrated drug targeting methodology in accordance with the present invention.
  • a metabolic network of a particular microorganism is constructed (A), from which essential metabolite analysis is predicted using essential metabolite analysis based on metabolic flow analysis (B). From this, the elimination of circulating metabolites (C), the consideration of the number of reaction formulas involved in the metabolites (D), the confirmation of the presence of essential metabolites and their involved reactions in human metabolism (E), etc. Predict the most effective drug targets of the microorganism (F).
  • step (c) determining a secondary essential metabolite by removing a circulation metabolite having no specificity with the target microorganism among the first essential metabolites determined in step (b);
  • step (d) may be selectively applied to “step (c) and / or (e); and (f)". Therefore, in another aspect, the present invention relates to a method for determining an essential metabolite according to the method of each step.
  • Step (f) is a step necessary to minimize adverse effects on the host of the drug, for example, the human body, and may shorten step (f) by performing steps (c) and (e). Therefore, in the case of performing step (f) in view of such efficiency, step (c) and step (e) can be selected individually or simultaneously. Most preferably, all the steps (c), (e) and (f) are performed.
  • step (d) may alternatively be carried out as a method devised in the present invention to significantly reduce the number of drug targets more effectively.
  • the method of one preferable aspect of this invention is as follows. That is, the present invention
  • step (c) determining a secondary essential metabolite by removing a circulation metabolite having no specificity with the target microorganism among the first essential metabolites determined in step (b);
  • step (d) determining the third essential metabolite in consideration of the number of enzymatic schemes involved and the number of enzymatic schemes consumed among the secondary essential metabolites determined in step (c);
  • step (e) selecting only those which are not present in the metabolism of the host among the third essential metabolites determined in step (d) and determining the fourth essential metabolite;
  • step (f) if all of the enzymes consuming the fourth essential metabolites determined in step (e) do not have homology with the host protein, the corresponding metabolites are determined as the fifth essential metabolite, and the fifth essential metabolite Selecting an enzyme involved in the drug target enzyme of the target microorganism.
  • Acinetobacter genus microorganisms for example, Acinetobacter baumannii
  • a method for screening drug target enzymes of the genus Acinetobacter comprising the following steps:
  • step (c) Of the primary essential metabolites determined in step (b), the secondary essential metabolite is removed by removing a circulation metabolite having no specificity with the microorganisms of the genus Acinetobacter. Determining;
  • step (d) determining the third essential metabolite in consideration of the number of enzymatic schemes involved and the number of enzymatic schemes consumed among the secondary essential metabolites determined in step (c);
  • step (e) selecting only those which are not present in the metabolism of the host among the third essential metabolites determined in step (d) and determining the fourth essential metabolite;
  • step (f) if all of the enzymes consuming the fourth essential metabolites determined in step (e) do not have homology with the host protein, the corresponding metabolites are determined as the fifth essential metabolite, and the fifth essential metabolite Selecting an enzyme involved in the drug target enzyme of the microorganism of the genus Acinetobacter.
  • step (d) may be selectively applied to the "step (c) and / or (e); and (f)".
  • step (d) may be selectively applied to the "step (c) and / or (e); and (f)".
  • Vibrio sp Microorganisms, for example, Vibrio vulnificus were used.
  • Vibrio includes not only Vibrio bulnipius, but also Vibrio cholera, Vibrio hemoritis, and the like.
  • a method for screening a drug target enzyme of Vibrio genus microorganism comprising the following steps:
  • step (c) Among the primary essential metabolites determined in step (b), the secondary essential metabolite is determined by removing a circulation metabolite having no specificity with Vibrio genus microorganisms. step;
  • step (d) determining the third essential metabolite in consideration of the number of enzymatic schemes involved and the number of enzymatic schemes consumed among the secondary essential metabolites determined in step (c);
  • step (e) selecting only those which are not present in the metabolism of the host among the third essential metabolites determined in step (d) and determining the fourth essential metabolite;
  • step (f) if all of the enzymes consuming the fourth essential metabolites determined in step (e) do not have homology with the host protein, the corresponding metabolites are determined as the fifth essential metabolite, and the fifth essential metabolite Selecting an enzyme involved in the drug target enzyme of the microorganism of Vibrio genus.
  • step (d) may be selectively applied to the "step (c) and / or (e); and (f)".
  • step (d) may be selectively applied to the "step (c) and / or (e); and (f)".
  • the present invention in another aspect, relates to a method for drug screening against a microorganism of the present invention.
  • step (e) selecting a compound candidate group having structural similarity to the essential metabolite in step (d) from the compound library using the Tanimoto coefficient;
  • step (c) determining a secondary essential metabolite by removing a circulation metabolite having no specificity with the target microorganism among the first essential metabolites determined in step (b);
  • step (d) determining the third essential metabolite in consideration of the number of enzymatic schemes involved and the number of enzymatic schemes consumed among the secondary essential metabolites determined in step (c);
  • step (e) selecting only those which are not present in the metabolism of the host among the third essential metabolites determined in step (d) and determining the fourth essential metabolite;
  • step (f) if all of the enzymes consuming the fourth essential metabolites determined in step (e) have no homology with the host protein, determining the essential metabolites as the fifth essential metabolite;
  • step (g) selecting a compound candidate group having structural similarity to the fifth essential metabolite in step (e) from the compound library using a Tanimoto coefficient;
  • screening drugs by administering each of the selected compound candidate groups to target microorganisms to determine whether they inhibit growth.
  • Tanimoto coefficient through a known tool including a pipeline for selecting a compound having a structure similar to a specific substance It may be used, specifically characterized by selecting a compound candidate group having a Tanimoto coefficient of 0.5 to 1.
  • the compound having a growth inhibitory effect of at least 80% compared to the control group is characterized by screening with a drug against the microorganism.
  • Acinetobacter in microorganisms, such as one embodiment used the Acinetobacter baumannii (Acinetobacter baumannii). Accordingly, in one aspect of the present invention, there can be provided a method for drug screening of the genus Acinetobacter, comprising the following steps:
  • step (c) Of the primary essential metabolites determined in step (b), the secondary essential metabolite is removed by removing a circulation metabolite having no specificity with the microorganisms of the genus Acinetobacter. Determining;
  • step (d) determining the third essential metabolite in consideration of the number of enzymatic schemes involved and the number of enzymatic schemes consumed among the secondary essential metabolites determined in step (c);
  • step (e) selecting only those which are not present in the metabolism of the host among the third essential metabolites determined in step (d) and determining the fourth essential metabolite;
  • step (f) if all the enzymes consuming the fourth essential metabolites determined in step (e) do not have a homology with the host protein, determining those essential metabolites as the fifth essential metabolite;
  • step (g) selecting a compound candidate group having structural similarity to the fifth essential metabolite in step (f) from the compound library by using Tanimoto coefficients;
  • Microorganisms for example, Vibrio vulnificus were used.
  • a method for drug screening of Vibrio genus microorganisms comprising the following steps:
  • step (c) Among the primary essential metabolites determined in step (b), the secondary essential metabolite is determined by removing a circulation metabolite having no specificity with Vibrio genus microorganisms. step;
  • step (d) determining the third essential metabolite in consideration of the number of enzymatic schemes involved and the number of enzymatic schemes consumed among the secondary essential metabolites determined in step (c);
  • step (e) selecting only those which are not present in the metabolism of the host among the third essential metabolites determined in step (d) and determining the fourth essential metabolite;
  • step (f) if all the enzymes consuming the fourth essential metabolites determined in step (e) do not have a homology with the host protein, determining those essential metabolites as the fifth essential metabolite;
  • step (g) selecting a candidate compound group having structural similarity to the fifth essential metabolite in step (f) from the compound library by using Tanimoto coefficient;
  • Methodabolism means a series of activities related to the energy activities of living things. That is, a series of activities that synthesize various metabolites necessary for life's activities through various biosynthesis through digestion that absorbs energy sources from the outside and converts them into the energy forms that are most readily available to life. Included in The first of the biological networks studied is this "metabolic network".
  • the first step in the present invention is to build a metabolic network of the target microorganism, to build a network consisting of all metabolites and reactive enzymes by collecting biochemical reactions occurring inside and outside the cell.
  • the target microorganism for constructing the metabolic network may be Escherichia coli or pathogenic microorganism, and any pathogenic microorganism may be used without particular limitation.
  • Acinetobacter Acinetobacter
  • Acinetobacter baumannii Acinetobacter baumannii
  • Vibrio Vibrio
  • Vibrio nipi carcass Vibrio vulnificus
  • a pathogenic microorganism is a microorganism having infectivity determined by pathogens, pathogens, pathogens, infectious pathways, and host susceptibility caused by toxins, enzymes, and other products produced by microorganisms, and may include various viruses, bacteria, and fungi. And they can be transmitted to various organisms such as animals and plants.
  • a metabolic network of microorganisms is established.
  • Acinetobacter baumannii (AB) is a gram-negative bacillus named after integrating two strains of Acinetobacter calcoaceticus and anitratus in the past, and has a wide range of bacteriological characteristics that make it possible to use various energy sources. It can be grown at or at pH and is found in samples taken from almost all soils and fresh water. Acinetobacter baumannii, which has this characteristic, has been reported as an important causative agent of hospital infections in many hospitals. Once hospital infections occur, they usually survive long-term in environments where bacteria are difficult to survive, resulting in high antibiotic resistance and resistance.
  • A. baumannii Due to its characteristics, it is difficult to treat, and as a result, the mortality rate caused by the causative organism also increases, which has recently emerged as an important pathogen.
  • A. baumannii is known to cause pneumonia associated with respirators, wound infections in burn patients, and sepsis.
  • the Acinetobacter genus microbial metabolic network construction used in an example of the present invention can be made based on a gene group consisting of the following genes:
  • Vibrio causes a variety of infections in humans as a kind of pathogenic microorganisms present in the sea and the estuary as a facultative anaerobic gram-negative bacilli, and are isolated from fresh water, rivers, ponds and lakes. More than 30 species belong to the genus Vibrio, 12 of which infect humans. Intestinal infections are the most common causative agents of V. cholerae and V. parahaemolyticus . Intestinal infections such as blood, wounds, eyes, ears, and bile can also occur. In Korea, Vibrio sepsis often occurs in summer, which is caused by V. vulnificus , which is mainly caused by cirrhosis and cancer patients and has a poor prognosis. .
  • the Vibrio vulnificus is mainly found in estuaries and is a pathogenic microorganism that infects a variety of animals and seafood, including humans (Gulig et al., J. Mcirobiol., 43: 118, 2005). Ingestion of seafood infected with V. vulnificus or contact with the microorganisms of the human body can cause sepsis, gastroenteritis and wound infection. In particular, V. vulnificus is known to be very fast in human body when infected. Contact with the pathogen can cause death within 24 hours. It is known that mortality from sepsis is up to 75%, and mortality from wound infections is reported to be up to 50%.
  • V. vulnificus the genome sequence translation of the two strains is completed (Chen et al., Genome Res. , 13: 2577, 2003), and therefore, the present inventors use partial metabolic flow analysis techniques.
  • This study examined the metabolism of V. vulnificus from the whole point of view, not the strain manipulation, and found the possibility of developing a method to accurately predict the drug target of pathogenic microorganisms by identifying the effects of manipulation of specific genes on the overall metabolic flow.
  • the Vibrio genus microbial metabolic network construction used in the example of the present invention may be made based on a gene group consisting of the following genes:
  • metabolic flow analysis is performed on the established metabolic network of the microorganism, which is to determine the essential metabolite of the microorganism primarily (called a primary essential metabolite).
  • the metabolic network of the constructed microorganism including all the metabolites constituting the constructed metabolic network model, the metabolic pathway of the metabolite and the stoichiometric matrix S in the metabolic pathway.
  • S ij the stoichiometric coefficient of the i-th time in the j-th reaction metabolite
  • the change in the metabolite concentration X over time can be represented as the sum of the flows of all metabolic reactions. Assuming that the amount of change of X with time is constant, i.e., if the amount of change of X is 0, the amount of change of the metabolite concentration with time under the quasi-steady state may be defined by Equation 1 above.
  • the reaction scheme to be optimized ie maximized or minimized, is set as the objective function and the metabolic flow in the cell is predicted using linear programming (Kim et al., Mol Biosyst. 4 (2)). : 113, 2008).
  • the cell growth rate is optimized by representing the constituents of the cells in matrix S and setting the scheme as the objective function. In other words, when applying the linear programming method, the objective function is set to maximize cell growth rate.
  • the metabolic flow analysis should be carried out on the assumption that all the nutrients necessary for the cell to grow can be taken. This is because when pathogenic microorganisms grow in the host, various nutrients can be taken from the host.
  • the enzyme reaction may appear to be essential only under certain conditions, but if metabolic flow analysis is applied on the assumption that all the nutrients can be ingested, it is possible to predict the essential enzyme reaction at all times.
  • the nutrients used were 2-Phospho-D-glycerate, 3-Phospho-D-glycerate, Acetate, Adenosine, 2 -Oxoglutarate, L-Alanine, L-Arginine, L-Asparagine, L-Aspartate, Betaine, Benzoate, Choline, Citrate, CO 2 , Cytosine, L-Cysteine, Cytidine, D-alanine, Deoxyadenosine, Deoxycytidine, D-Glutamate, Deoxyguanosine, D-Serine, Thymidine, Deoxyuridine, Ethanolamine, Formate, D-fructose, Fumarate, alpha-D-Glucose, L-Glutamine, D-Gluconate, L-Glutamate, Glycolate, Glycine, Gu
  • the nutrients used were (S) -Lactate, (S) -Malate, 2-Oxoglutarate, 2-Phospho -D-glycerate, 3-Phospho-D-glycerate, Acetate, Adenosine, alpha, alpha-Trehalose, alpha-D-Glucose, Choline, Citrate, CO 2 , Cytidine, Cytosine, D-alanine, Deoxyadenosine, Deoxycytidine, Deoxyguanosine, Deoxyuridine, D-Fructose, D-Gluconate, D-Glutamate, D-Mannitol, Fumarate, Glycerol, Glycine, Guanosine, Isocitrate, Isomaltose, L-Alanine, L-Arginine, L-Asparagine, L-Aspartate, L-Cystein
  • the method of determining the cell growth rate according to a specific gene deletion uses a method of inactivating each corresponding reaction scheme. Suppressing these enzyme reactions is based on the assumption that it is impossible to consume or produce the specific metabolites involved in these enzymes, which will eventually stop the cell growth of the target microorganism.
  • Suppressing these enzyme reactions is based on the assumption that it is impossible to consume or produce the specific metabolites involved in these enzymes, which will eventually stop the cell growth of the target microorganism.
  • the present invention by defining the 'essentiality' of each metabolite and examining the properties of each metabolite, it is easy to identify the phenomenon of cell growth caused by the deletion of two or more genes. That is, the present invention provides a method of defining and using 'essentiality' of metabolites constituting the metabolic network of the target microorganism as follows.
  • the 'essentiality' of metabolites is the effect of cells on the growth of cells when they are not consumed by metabolism.
  • the rate of cell growth for each metabolite under certain conditions is determined by metabolic flow analysis.
  • the necessity of metabolites can be determined by investigating (FIG. 4) (Kim et al., Proc. Natl. Acad. Sci. USA , 104: 13638, 2007).
  • the metabolic flow value of the corresponding reaction equation is fixed to zero. In this case, if the growth rate of the cell is 0 is selected as an essential metabolite.
  • V jm represents the metabolic flow value of the consumption equation.
  • Essential metabolite analysis applies Equation 2 as an additional constraint while simultaneously blocking (deleting) all metabolic reactions consuming each metabolite in the stoichiometric matrix.
  • the metabolic flow value of the consumption equation By fixing the metabolic flow value of the consumption equation to 0, the case where the cell growth rate is 0 is selected as an essential metabolite. In other words, if there is no metabolic flow of essential metabolite, the cells of the microorganism do not grow to determine the essentiality.
  • the reason for not inactivating a metabolite produced without consuming a given metabolite is that the metabolite that produces the metabolite, even if the metabolite is non-essential Because it is also possible to produce other essential metabolites, if cell growth is inhibited due to inactivation of the metabolic reaction, it may be misunderstood that a non-essential metabolite is essential.
  • the primary essential metabolite of AYE ( Acinetobacter baumannii AYE) obtained through metabolic flow analysis using Equation 1 and Equation 2 is (R) -4′-Phosphopantothenoyl-L-cysteine, (R ) -pantoate, (R) -Pantothenate, 1,4-dihydroxy-2-naphthoate, 1-Acyl-sn-glycerol 3-phosphate, 1-Deoxy-D-xylulose 5-phosphate, 2,3,4,5- Tetrahydrodipicolinate, 2,3-Dihydrodipicolinate, 2,5-Diamino-6-hydroxy-4- (5'-phosphoribosylamino) -pyrimidine, 2-Acyl-sn-glycero-3-phosphoethanolamine, 2-Amino-4-hydroxy-6 -(D-erythro-1,2,3-trihydroxypropyl) -7,8-dihydropteridine, 2-Amino-4-hydroxy-6-
  • the first essential metabolite of Vibrio vulnificus obtained through the metabolic flow analysis step using Equations 1 and 2 is (R) -4′-Phosphopantothenoyl-L-cysteine, (R) -pantoate, (R) -Pantothenate, 1,4-dihydroxy-2-naphthoate, 1-Deoxy-D-xylulose 5-phosphate, 1-Hydroxy-2-methyl-2-butenyl 4-diphosphate, 2, 3,4,5-Tetrahydrodipicolinate, 2,3-Dihydrodipicolinate, 2,5-Diamino-6-hydroxy-4- (5'-phosphoribosylamino) -pyrimidine, 2-Acyl-sn-glycero-3-phosphoethanolamine (L-1 -Lysophosphatidylethanolamine), 2-Amino-4-hydroxy-6- (D-erythro-1,2,3-trihydroxypropyl) -7,8-dihydropter
  • circulation metabolite (currency metabolite) involved in a number of enzyme reactions of various organisms.
  • Information on the metabolites in circulation is published in a paper published in Bioinformatics in 2003 (Ma and Zeng, Bioinformatics, 19: 1423, 2003), which do not have the specificity unique to the target microbial pathogen. Remove from the list of primary essential metabolites on the computer.
  • the result of removing the distribution metabolite from the first essential metabolite was named as a second essential metabolite.
  • At least two or more of the secondary essential metabolites are involved in the enzyme reaction, while at least two or more simultaneously name the metabolite when consuming the essential metabolite as the third essential metabolite.
  • This method has the advantage of simultaneously targeting the consuming enzymes when using a metabolite analogue (metabolite analogue) as a drug.
  • the biggest problem of anti-pathogen drugs is that the resistance of the pathogen to the drug occurs quickly, which is mainly caused by a single endogenous mutation of the enzyme target enzyme gene, thus the drug target gene group of the present invention.
  • the combination has the advantage of being able to simultaneously target several places of the target microbial pathogen metabolism to minimize the resistance of the pathogen, and to reliably control the growth of the pathogen in the host.
  • Acinetobacter Baumani or Vibrio Bulnipicus which is used as an embodiment in the present invention, is a kind of multi-drug resistant (MDR) infectious bacterium that is resistant to many drugs. It suggests that it may be an effective method for multidrug resistant pathogenic microorganisms.
  • MDR multi-drug resistant
  • the strategy is to ultimately disable the intake of essential metabolites from pathogens, thereby simultaneously inactivating all of the surrounding reactions, so even if the reactions are carried out by isoenzymes, it is not a problem.
  • the remaining metabolites are named 5th essential metabolites.
  • the host is a human
  • the essential metabolites predicted through the metabolic flow analysis are further screened based on the homology between the enzymes and the host proteins related to their consumption equations to further reduce the number of possible essential metabolites. .
  • drugs developed by targeting specific genes or enzymes act on the basis of the 'sequence' of the genes or enzymes. Therefore, if the genes or enzymes in these sequences are present in humans, the drugs also act on human proteins. May cause
  • the genomic information of the host is preferable to use as a database.
  • the BLASTP program may be used when using an amino acid sequence, or the BLAST program may be used when using a gene sequence.
  • any data can be used as long as those skilled in the art can identify homology regardless of amino acid sequence or gene sequence.
  • the present invention used the BLASTP program.
  • the human genomic information is used as a database.
  • the genes and amino acid sequences encoding all the enzymes consuming each of the essential metabolites further selected in the present invention are significantly different from those of the host protein, resulting in structurally different functionalities from the host protein. do.
  • step (4-2) can be selectively applied to step (4-1) and / or step (4-3) and step (4-4). have.
  • the pathogenic microorganism-specific essential metabolites can be finally determined, and the enzymes involved in these essential metabolites are determined as drug target enzyme groups.
  • the enzymes involved in these essential metabolites are determined as drug target enzyme groups.
  • Genes encoding drug target enzymes can be determined as a drug target gene family.
  • the fifth essential metabolite of AYE ( Acinetobacter baumannii AYE) used in the example of the present invention is 2-Amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine, D-Glutamate, 2,3-Dihydrodipicolinate, 2-Amino -4-hydroxy-6- (D-erythro-1,2,3-trihydroxypropyl) -7,8-dihydropteridine, 3-Dehydroshikimate, 1-Deoxy-D-xylulose 5-phosphate, 3-Dehydroquinate, 2-Dehydro- 3-deoxy-D-octonate, 4-Aminobenzoate and the like,
  • Drug target enzymes involved in metabolism include 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine, pyrophosphokinase, dihydropteroate synthase, glutamate racemase, UDP-N-acetylmuramoylalanine--D-glutamate ligase, dihydrodipicolinate reductase, dihydroneopterin aldolase, alkaline phosphatase D precursor, 3-dehydroquinate dehydratase II, catabolic 3-dehydroquinate dehydratase (3-dehydroquinase), shikimate 5-dehydrogenase, quinate / shikimate dehydrogenase, 3-dehydroshikimate dehydratase, 1-deoxy-D-xylulose-5-phosphate reductoisomerase, pyridoxine 5-phosphate synthase, 3-deoxy-manno-octulosonate cytidylyltransferase, dihydropter
  • Drug target gene groups include ABAYE0036, ABAYE0082, ABAYE0377, ABAYE0807, ABAYE0811, ABAYE0945, ABAYE1417, ABAYE1418, ABAYE1539, ABAYE1581, ABAYE1682, ABAYE1683, ABAYE1685, ABAYE2076, AYEYE95, ABAYE3176, ABA3, 355
  • the fifth essential metabolite of Vibrio vulnificus used in one embodiment of the present invention is 1-deoxy-D-xylulose 5-phosphate, 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine , 2,3-dihydrodipicolinate, 4-aminobenzoate, D-glutamate and the like,
  • Drug target enzymes involved in their metabolism include 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase, dihydropteroate synthase, glutamate racemase, UDP-N-acetylmuramoylalanine--D-glutamate ligase, dihydrodipicolinate reductase, 1-deoxy-D -xylulose-5-phosphate reductoisomerase, pyridoxine 5-phosphate synthase, etc.,
  • VV10567, VV10580, VV11175, VV11568, VV11644, VV11691, VV11866 and the like can be determined.
  • the present invention provides a drug target enzyme candidate and a gene encoding the drug target enzyme of the above-described microorganisms or genes encoding the same, which are obtained by the screening method, which are involved in the metabolism of essential metabolites at each step. Provide gene families.
  • step (d) drug target enzyme candidates involved in the primary essential metabolite determined by the metabolic flow analysis of step (b) and the gene group encoding the same; drug target enzyme candidates involved in the secondary essential metabolite determined by removing the circulation metabolite of step (c) and the gene group encoding the same;
  • step (d) at least three or more enzyme reactions, and at least two or more at the same time the drug target enzyme candidates and genes encoding the enzymes involved in the selected third essential metabolite when the essential metabolite is consumed group; drug target enzyme candidates involved in the fourth essential metabolite determined by selecting only those not present in the metabolism of the host in step (e) and the gene group encoding the same;
  • step (f) a drug target enzyme candidate involved in the fifth essential metabolite determined by selecting a case where there is no homology with the host protein among enzymes related to metabolism of the fourth essential metabolite and a gene group encoding the same.
  • the present invention also relates to a method of using the determined enzyme group and the gene group encoding the same as the drug target of the target microorganism.
  • a group of enzymes of -5-phosphate reductoisomerase, pyridoxine 5-phosphate synthase, or the gene groups VV10567, VV10580, VV11175, VV11568, VV11644, VV11691, and VV11866 encoding the same can be used as drug targets of Vibrio vulnificus . Can be.
  • the structure of the fifth essential metabolite or the final essential metabolite obtained by the above method can be used to select compounds having similar structures from the compound library as drug candidates.
  • the Tanimoto coefficient is used.
  • the microorganisms are treated to confirm whether the growth of the microorganisms is examined through experiments.
  • the structural analogous compound inhibits at least 80% of the concentration of the microorganism relative to the highest concentration of the control standard microorganism that has not been treated with the compound, the structural analogous compound may be considered to be effective as an anti-pathogen drug candidate.
  • MIC minimum microbial concentration
  • Such drug target enzymes and drug target genes according to the present invention obtain only the next effective drug target candidate groups for pathogenic diseases, and are useful for the treatment and prevention of diseases caused by microbial pathogens.
  • the present invention relates to an antimicrobial composition against Vibrio genus containing the compound of Formula 1, a derivative thereof, or a salt as an active ingredient. Furthermore, it includes all possible solvates, hydrates or racemates that can be prepared therefrom.
  • Vibrio not only Vibrio bulnipius, but also Vibrio cholera, Vibrio hemoritis, and the like will be included.
  • the antimicrobial means having the growth inhibitory ability of Vibrio uniphycus, and furthermore, is a concept including both growth and infection prevention, growth inhibition, and / or killing action.
  • antimicrobial compositions include all forms of food, cosmetic or pharmaceutical compositions.
  • the content of the drug in the composition of the present invention is 0.01% to 100% by weight.
  • dragees, pills, gelatin capsules, syrups, gels which comprise a carrier which can be ingested directly with water or by any other known means, containing a dosage of 0.001 to 100% of the composition.
  • supplements in the form of creams or peppermint drops This supplement additionally contains sweeteners, stabilizers, additives, flavors and pigments.
  • the composition may be a cosmetic preparation containing a skin active compound known to those skilled in the art.
  • the present invention also relates to a cosmetic composition containing the above preliminary composition.
  • the content of the drug in the composition may comprise 0.01% by weight or more.
  • Other cosmetically active ingredients may also be added.
  • the composition can be added to the composition also emulsifiers, excipients, pigments, flavors or opacifiers.
  • the composition may be a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a drug.
  • the drug may also be prepared as a medicament by adding 0.01 to 100 parts by weight to one or more pharmaceutically acceptable carriers relative to the total weight.
  • the carrier may include, but is not limited to, saline, buffered saline, water, glycerol and ethanol, and any suitable agent known in the art (Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA) may be used. .
  • the composition may be prepared in the form of oral preparations, granules, powders, syrups, solutions, liquid extracts, emulsions, suspensions, acupuncture tablets, injections, capsules, creams, troches, pasta preparations, oral or It can be used parenterally.
  • Dosage of the composition is a conventional dosage, for example, from 1 to 100 mg of the drug can be used per day.
  • the dosage is not limited thereto, and may be differently applied depending on the age, sex, condition, absorbency of the active ingredient in the body, inactivation rate, type of disease, and the like.
  • the present invention also relates to a disinfectant comprising a drug as an active ingredient.
  • the disinfectant is a concept including all killing, growth or infection of pathogenic microorganisms, and antibacterial action. It is a natural disinfectant that is harmless to human body by applying strong sterilization function, sterilization of kitchen utensils (cutting board, knife, pot, chopsticks, cutlery, container, various utensils), personal cleaning products (oral cleaner, vaginal cleaner, soap, shampoo, Toothpaste), natural water disinfectant, such as sterilization disinfection of the environment surrounding the facility, including the cooling water sterilization disinfection of the air conditioner, air conditioner antibacterial filter, hospitals and homes. It can also be used as a disinfectant for water pipes, hot water tanks, water tanks, or humidifiers in hospitals and homes.
  • salts may be used in the form of a pharmaceutically acceptable salt, and acid salts formed by pharmaceutically acceptable free acid are useful as salts.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Dioates, aromatic acids, aliphatic and
  • non-toxic organic acids such as aromatic sulfonic acids.
  • Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide.
  • the acid addition salts according to the present invention can be dissolved in conventional methods, for example, by dissolving Formula 1 or a derivative thereof in an excess aqueous solution of an acid, which salts are water-miscible organic solvents such as methanol, ethanol, acetone or acetonitrile. Can be prepared by precipitation.
  • the acid or alcohol in the drug of Formula 1 and water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be manufactured by suction filtration.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt.
  • Corresponding silver salts are also obtained by reacting alkali metal or alkaline earth metal salts with a suitable negative salt (eg, silver nitrate).
  • the composition may be various oral or parenteral dosage forms when used as a pharmaceutical composition.
  • diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used.
  • Solid form preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which form at least one excipient such as starch, calcium carbonate, sucrose or lactose (at least one compound). lactose) and gelatin.
  • lubricants such as magnesium stearate, talc and the like are also used.
  • Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin, may be included.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like can be used.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • KEGG Kanehisa et al..Nucleic Acids Res , 34: D354, 2006
  • TransportDB (Ren et al., PLoS Comput. Biol ., 1: e27, 2005)
  • MetaCyc (Caspi et al. Nucleic Acids Res. , 36 (D623, 2008)
  • the constructed metabolic network of A. baumanii AYE consists of 891 biochemical schemes and 778 metabolites, and the information of this metabolic network contains the following 650 gene information.
  • the predicted drug targets were selected from these schemes.
  • R035, R036, R044, R046, R052, R068, R069, R070, R071, R095, R108, R157, R160, R227, R239, R319, R320, R328, R329, R330, R346, R472, R608, R619, R621, R635, R649, R673, R745, R746, R747, and R748 are reactions without genes assigned to genomic information.
  • the constructed metabolic network of V. vulnificus CMCP6 consists of 945 biochemical schemes and 765 metabolites, and the information of this metabolic network contains the following 672 gene information. The predicted drug targets were selected from these schemes.
  • R002, R150, R196, R201, R233, R237, R238, R239, R240, R241, R413, R505, R619, R659, R660, R661, and R705 have no genes assigned to genomic information.
  • the secondary essential metabolites were associated with at least three or more reaction schemes, but two or more reaction schemes were further selected only to consume those essential metabolites, thereby obtaining 97 tertiary essential metabolites.
  • Example 2- (2) For the essential metabolite determined through metabolic flow analysis in Example 2- (2), those corresponding to the distribution metabolite were removed to obtain 162 secondary essential metabolites.
  • ACACP ACCOA, ACP, AHHMP, AHTD, ARG, ASN, ASP, ASPSA, bALA, C120ACP, C140ACP, C150ACP, C160ACP, C161ACP, C180ACP, C181ACP, CDPDG, CHOR, CYS, DALA, DATP, DCTP, DGLU, DGTP DHAP, DHDP, DHF, DHN, DHSK, DMK, DTMP, DTTP, DX5P, E4P, F6P, FMN, FUM, G1P, G3P, GL3P, GLY, GLYCOGEN, HIS, ILE, IPP, LEU, LYS, MALACP, MDAPIM, MET, MK, MKH2, NACN, OBUT, OIVAL, OPP, P5P, PABA, PE, PEP, PG, PHE, PHT, PPAACP, PPACOA, PRO, PRPP
  • a total of 352 structure-like compounds having a Tanimoto coefficient of 0.5 to 1.0 were selected as drug candidates from the compound library.
  • 100 ⁇ l was added to each well of a 100-well plate.
  • Mueller Hinton's complex liquid medium was added, and metabolic microorganisms were cultured in each well.
  • MIC minimal inhibitory concentration
  • the present invention relates to a method for predicting a drug target of a microorganism and screening for a drug candidate compound capable of efficiently inhibiting microbial growth.
  • the present invention is based on the results of essential metabolite analysis based on metabolic flow analysis, including pathogens. Only potential next effective drug target candidates for diseases caused by various microorganisms are obtained, which is useful for the treatment and prevention of diseases caused by the pathogen microorganisms. In particular, it is useful for the treatment and prevention of diseases caused by such pathogenic microorganisms by screening new drug compounds against pathogens that are multi-drug resistant, such as Acinetobacter Baumani, Vibrio Bulnipicus, and the like.

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Abstract

La présente invention concerne une méthode de prédiction de cibles de médicament et de criblage de médicaments destinés à détecter des microorganismes pathogènes au moyen de métabolites essentiels. Plus particulièrement, la présente invention concerne une méthode de criblage d'enzymes cibles de médicament efficaces destinés à détecter des microorganismes pathogènes ou de gènes cibles de médicaments codant pour les enzymes. L'invention porte en outre sur une méthode de criblage de médicaments capables d'inhiber la croissance de microorganismes pathogènes. Ladite méthode comprend les étapes suivantes : sélection de microorganismes cibles ; construction d'un modèle de réseau métabolique pour les microorganismes sélectionnés ; prédiction du métabolite essentiel à la croissance cellulaire au moyen d'une analyse du caractère essentiel du métabolite ; suppression d'un métabolite de circulation, et suppression d'un métabolite essentiel, dont le nombre de réactions de sortie est inférieur au nombre de référence ; et sélection des métabolites essentiels restants et des métabolites essentiels de telle sorte que les enzymes qui consomment les métabolites essentiels ne soient pas présentes dans le métabolisme d'un hôte.
PCT/KR2010/006469 2009-09-18 2010-09-20 Méthode de prédiction de cibles de médicament et criblage de médicaments destinés à détecter des microorganismes pathogènes au moyen de métabolites essentiels WO2011034397A2 (fr)

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